Cellular communication is necessary for organizing multicellular organisms,and is critical in tumorigenesis and progression.Immune and tumor cells use the cGAS-STING mechanism to sense and respond to genomic instabili...Cellular communication is necessary for organizing multicellular organisms,and is critical in tumorigenesis and progression.Immune and tumor cells use the cGAS-STING mechanism to sense and respond to genomic instability,DNA damage,and mitochondrial dysfunction induced by extra-and intracellular stresses.展开更多
There are errors in Figure 1D1 on page 94.Specifically,RAB22A-induced autophagosomes were inadvertently marked in Figure 1D.We have revised Figure 1 to correct the errors.Of note,the errors do not impact the conclusio...There are errors in Figure 1D1 on page 94.Specifically,RAB22A-induced autophagosomes were inadvertently marked in Figure 1D.We have revised Figure 1 to correct the errors.Of note,the errors do not impact the conclusion of this article.We apologize for the errors and for any resulting confusion.展开更多
Loss of TGF-β-mediated growth suppression is a major contributor to the development of cancers,best exemplified by loss-offunction mutations in genes encoding components of the TGF-βsignaling pathway in colorectal a...Loss of TGF-β-mediated growth suppression is a major contributor to the development of cancers,best exemplified by loss-offunction mutations in genes encoding components of the TGF-βsignaling pathway in colorectal and pancreatic cancers.Alternatively,gain-of-function oncogene mutations can also disrupt antiproliferative TGF-βsignaling.However,the molecular mechanisms underlying oncogene-induced modulation of TGF-βsignaling have not been extensively investigated.Here,we show that the oncogenic BCR-ABL1 of chronic myelogenous leukemia(CML)and the cellular ABL1 tyrosine kinases phosphorylate and inactivate Smad4 to block antiproliferative TGF-βsignaling.Mechanistically,phosphorylation of Smad4 at Tyr195,Tyr301,and Tyr322 in the linker region interferes with its binding to the transcription co-activator p300/CBP,thereby blocking the ability of Smad4 to activate the expression of cyclin-dependent kinase(CDK)inhibitors and induce cell cycle arrest.In contrast,the inhibition of BCR-ABL1 kinase with Imatinib prevented Smad4 tyrosine phosphorylation and re-sensitized CML cells to TGF-β-induced antiproliferative and pro-apoptotic responses.Furthermore,expression of phosphorylation-site-mutated Y195F/Y301F/Y322F mutant of Smad4 in Smad4-null CML cells enhanced antiproliferative responses to TGF-β,whereas the phosphorylation-mimicking Y195E/Y301E/Y322E mutant interfered with TGF-βsignaling and enhanced the in vivo growth of CML cells.These findings demonstrate the direct role of BCR-ABL1 tyrosine kinase in suppressing TGF-βsignaling in CML and explain how Imatinib-targeted therapy restored beneficial TGF-βanti-growth responses.展开更多
Although the unique organization of vertebrate cone mosaics was first described long ago,both their underlying molecular basis and physiological significance are largely unknown.Here,we demonstrate that Crumbs protein...Although the unique organization of vertebrate cone mosaics was first described long ago,both their underlying molecular basis and physiological significance are largely unknown.Here,we demonstrate that Crumbs proteins,the key regulators of epithelial apical polarity,establish the planar cellular polarity of photoreceptors in zebrafish.Via heterophilic Crb2a-Crb2b interactions,the apicobasal polarity protein Crb2b restricts the asymmetric planar distribution of Crb2a in photoreceptors.The planar polarized Crumbs proteins thus balance intercellular adhesions and tension between photoreceptors,thereby stabilizing the geometric organization of cone mosaics.Notably,loss of Crb2b in zebrafish induces a nearsightedness-like phenotype in zebrafish accompanied by an elongated eye axis and impairs zebrafish visual perception for predation.These data reveal a detailed mechanism for cone mosaic homeostasis via previously undiscovered apical-planar polarity coordination and propose a pathogenic mechanism for nearsightedness.展开更多
文摘Cellular communication is necessary for organizing multicellular organisms,and is critical in tumorigenesis and progression.Immune and tumor cells use the cGAS-STING mechanism to sense and respond to genomic instability,DNA damage,and mitochondrial dysfunction induced by extra-and intracellular stresses.
文摘There are errors in Figure 1D1 on page 94.Specifically,RAB22A-induced autophagosomes were inadvertently marked in Figure 1D.We have revised Figure 1 to correct the errors.Of note,the errors do not impact the conclusion of this article.We apologize for the errors and for any resulting confusion.
基金grants from NSFC(U21A20356,31730057,and 91540205)and ZNSF(LD21C070001)the Fundamental Research Funds for the Central Universities.L.W.was supported by a short-term predoctoral fellowship from the Graduate School of Zhejiang University for studying abroad.
文摘Loss of TGF-β-mediated growth suppression is a major contributor to the development of cancers,best exemplified by loss-offunction mutations in genes encoding components of the TGF-βsignaling pathway in colorectal and pancreatic cancers.Alternatively,gain-of-function oncogene mutations can also disrupt antiproliferative TGF-βsignaling.However,the molecular mechanisms underlying oncogene-induced modulation of TGF-βsignaling have not been extensively investigated.Here,we show that the oncogenic BCR-ABL1 of chronic myelogenous leukemia(CML)and the cellular ABL1 tyrosine kinases phosphorylate and inactivate Smad4 to block antiproliferative TGF-βsignaling.Mechanistically,phosphorylation of Smad4 at Tyr195,Tyr301,and Tyr322 in the linker region interferes with its binding to the transcription co-activator p300/CBP,thereby blocking the ability of Smad4 to activate the expression of cyclin-dependent kinase(CDK)inhibitors and induce cell cycle arrest.In contrast,the inhibition of BCR-ABL1 kinase with Imatinib prevented Smad4 tyrosine phosphorylation and re-sensitized CML cells to TGF-β-induced antiproliferative and pro-apoptotic responses.Furthermore,expression of phosphorylation-site-mutated Y195F/Y301F/Y322F mutant of Smad4 in Smad4-null CML cells enhanced antiproliferative responses to TGF-β,whereas the phosphorylation-mimicking Y195E/Y301E/Y322E mutant interfered with TGF-βsignaling and enhanced the in vivo growth of CML cells.These findings demonstrate the direct role of BCR-ABL1 tyrosine kinase in suppressing TGF-βsignaling in CML and explain how Imatinib-targeted therapy restored beneficial TGF-βanti-growth responses.
基金supported by National Natural Science Foundation of China projects (81770938 to J.Z. and 81570822 to K.Y.)the Zhejiang Provincial Natural Science Foundation project (LZ15H120001 to J.Z.)the Fundamental Research Funds for the Central Universities (2016FZA7010 and 2017FZA7001 to J.Z.)。
文摘Although the unique organization of vertebrate cone mosaics was first described long ago,both their underlying molecular basis and physiological significance are largely unknown.Here,we demonstrate that Crumbs proteins,the key regulators of epithelial apical polarity,establish the planar cellular polarity of photoreceptors in zebrafish.Via heterophilic Crb2a-Crb2b interactions,the apicobasal polarity protein Crb2b restricts the asymmetric planar distribution of Crb2a in photoreceptors.The planar polarized Crumbs proteins thus balance intercellular adhesions and tension between photoreceptors,thereby stabilizing the geometric organization of cone mosaics.Notably,loss of Crb2b in zebrafish induces a nearsightedness-like phenotype in zebrafish accompanied by an elongated eye axis and impairs zebrafish visual perception for predation.These data reveal a detailed mechanism for cone mosaic homeostasis via previously undiscovered apical-planar polarity coordination and propose a pathogenic mechanism for nearsightedness.
